MELAWOCORT1N TYPE 4 RECEPTOR AGONIST PIPERIDINOYLPYRROLIDINES This present invention relates to a certain class of compounds, and their pharmaceutical^ acceptable salts, solvates and prodrugs thereof, which are agonists at the melanocortin 4 (MC4) receptor, especially to selective MC4 agonist compounds, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. In particular the present invention relates to a class of MCR4 agonist plperkfinaylpyrrolidine compounds useful for the treatment of sexual dysfunctions, obesity, diabetes and other disorders. {The terms "MC4", "MC4 receptor", "MCF^*, "MC4-R", etc. are used interchangeably herein.] fttetanocor&is are peptides derived from prc-opiomelanocortins (POMC) that bind to and activate G-protesn coupled receptors (GPCR's) of the melanocortjn receptor family. Melanocortins regulate a diverse number of physiological processes including sexual function and sexual behaviour, food intake and metabolism. There are five melanocortin receptors that have been cloned, MCR1, MCR2, MCR3, MCR4, MCR5, and are expressed in various tissues. MCR1 is specifically expressed in melanocytes and melanoma celts, MCR2 is the ACTH receptor and is expressed in adrenal tissue, MCR3 is predominantly expressed in the brain and limbic system, MCR4 is widely expressed in the brain and spinal cord, and MCR5 is expressed in the brain and many peripheral tissues including skin, adipose tissue, skeletal muscle, and Lymphoid tissue. MCR3 may be involved in the control of sexual function, food intake and thermogenesis. MC4-R is a G-protein-r-coupled seven-transmembrane receptor primarily expressed in the hypothalamus, hippocampus, and thalamus (Gantz et al. 1993 J Biol Chem 268:15174—15179). The receptor is implicated in the central regulation of body weight: MC4-R is activated by a-melanocyte-stimulating hormone (MSH), which is derived from pro-opiomelanocortin and is inactivated by agouti gene-related protein (AGRP). o-MSH induces weight loss, whereas the ectopic expression of agouti protein results in obesity in the agouti mice (Fan etal. 1993 Nature 385:165-168; Lu et al. 1994 Nature 371:799-802). Additional evidence for the role of MC4-R in weight regulation stems from both a knockout model in mice (Huszar et al. 1997 Cell 88:131 -141) and haploinsufficiency mutations in humans (Vaisse et al. 1998 Nat Genet 20:113-114; Yeo et al. 1998 War Genef 20:111-112; Hinney et al. 1999 J Clin Endocrinol Metab 84:1483-1486). In MC4-fi-knockout mice, an increased body weight was discernible by age 5 wk. By age 15 wk, homozygous mutant females were, on average, twice as heavy as their wild-type liftermates, whereas homozygous mutant males were ""50% heavier than wild-type controls. Mice heterozygous for the MC4-R knockout showed a weight ga'n intermediate to that seen in wild-type and homozygous mutant littermates, thus demonstrating a gene dosage effect of MC4-R ablation on body-weight regulation. The food intake of homozygous mutants was increased by ~50% in comparison to that in wild-type sibs (Huszar etal. 1997 Cell88:131-141). IFrom Am. J. Hum. Genet, 65:1501-1507,1999]. MCR4activation has been shown to induce penile erection in rodents and MCR4 inactivation has been shown to cause obesity (reviewed in Hadley, 1999, Ann N Y Acad ScL, 885:1-21, Wikberg et al 2000, Pharmacol Res., 42(5), 393-420). Chaki and Nakazato, in Drugs Of The Future, 2004, 29(10): 1065-1074: refer to potential theraDeutic appfications for iigands acting at the MC4 receptor, international Patent Application publication numbers WO 2005/077935, WO 02/068387 and WO 02/068388, and International Patent Application PCT/ffl200&'002151 refer to certain piperidinylcarbonylpyrrolidines as MC4 agonists useful in treating sexual dysfunctions, obesity, diabetes and other disorders. The preceding publications are hereby incorporated by reference in their entirety, with regard to the therapeutic aspects of the MC4 agonists of this invention. Compounds of the present invention are useful in treating diseases, disorders or conditions responsive to activation of the MC4 receptor, including : male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and/or sexual pain disorder in females, mate erectile dysfunction; obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving); and diabetes mellitus (by enhancing glucose tolerance and/or decreasing insulin resistance). The compounds of the invention are potentially useful in treating further diseases, disorders or conditions including, but not limited to, hypertension, hyperBpidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, fever, inflammation, immune modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease, treatment of Lower Urinary Tract Dysfunction (including Urinary Incontinence -overactive bladder, increased daytime frequency, nocturia, urgency, urinary incontinence (any condition in which there is an involuntary leakage of urine), including stress urinary incontinence, urge urinary incontinence and mixed urinary incontinence, overactive bladder with associated urinary incontinence, enuresis, nocturnal enuresis, continuous urinary incontinence, situational urinary incontinence such as incontinence during sexual intercourse, and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)), and any other indications mentioned in the above-referenced patent applications-Compounds of the present invention are particularly suitable for treating female sexual dysfunction, male erectile dysfunction, obesity, diabetes, and conditions of Lower Urinary Tract Dysfunction. The terms "treating", "treat", or "treatment" as used herein are intended to embrace both prevention and control i.e., prophylactic, and palliative treatment of the indicated conditions. Desirable properties for MCR4 agonist compounds of the present invention include: desirable MCR4 agonist potencies as detailed hereinafter; selectivity for MCR4 agonism versus MCR1, and/or MCR5, and/or MCR3 as detailed hereinafter; both desirable MC4R agonist potency and selectivity for MCR4 versus, MCR1, and/or MCR5, and/or MCR3; good biopharmaceutical properties such as physical stability, solubility, oral bioavailability, appropriate metabolic stability, ability to displace AGRP from the MC4 receptor. The present invention provides for compounds of formula (% (Formula Removed) wherein one of X and Y is N and the other is CH, R is F, CI, CN, CF3 or methoxy, with tine proviso that when Y is N, R is not F or CI, R1 is phenyl, 2-pyridyl, C3-CB cycioalkyl or CHetCa-Ca cycioalkyl), whereini the ring moiety is optionally substituted by one or more substituents independently selected from F, CI, CN, methyl and methoxy, Rz is H, F or CI, with the proviso that when Y is N, Rz is not F or CI, Het is a 6-membered ring containing one or 2 N atoms, wherein (he ring is either aromatic, or contains 2 double bonds in the ring and a =0 substituent, which ring is optionally substituted by one or more substiluents independently selected from F, CI, OHr CN, methyl, ethyl, Nl-fe, NHCH3, N(CH3)2 and methoxy, or alternatively, Het is a 6-membered ring containing one or 2 N atoms fused at the 3,4-positions, relative to the attachment to the pyrrolidine ring, to a 5-membered aromatic ring containing one or two further N atoms, which 5-membered ring is optionally substituted by OH. and the pharmaceutical^ acceptable salts, solvates (including hydrates), and prodrugs thereof. Non-limiting examples of suitable "Hef groups are shown below: (Formula Removed) Preferably X is N and Y is CH. Preferably R is chtoro. Preferably R1 is phenyl optionally substituted by one or more substituents independently selected from F, CI, CN, methyJ and methoxy. More preferably R1 is phenyl, 4-chlorophenyl or 4-fluorophenyl. In an alternative embodiment R1 is preferably C3-C2-methylpyridazm-3(2H>-orie; S4(3S;4S)-3-(5^k)ropyTidin-2-y1)^a<3R/ffi^ t-yl]carbonyI}pyrrolidiri-1-yl3-2-niethylpyrida2in-3<2H>-o*ie; 6-[(3S,4S)^-(S-chloropyridin-2-yl)^Q;(3R14Rt5SH-cyckJhexyM4iydroxy-3,5-dim yljcaftonyl}pyrrolkJin-1 -ylJ-2-methylpyrida2in-3(2H)-one; (SR^R^SH-fKSS^SH^e-cfcloropyridazin^yl)^ fluoj-opheniyl)-3,5-dimethylpiperidin-4-ol; <3R,4R3S)-l-{[(3Sl4S)^5-chloropyrklm-2-yl}-1-(e^memoxypyridazin-3-yl)pyrrolidin-^^ cyclopropyJ-3,5-dlmethylp^)eridIn-4-ol; (SR^SSM-fl^S^Sy+^S-chloropyridin^-ylH-^fl fluwqphenyO-S^S-dlmethylpiperidMTi-A-ol; 6-[(3St4S>-3K5-ciitoropyridin-2-yl)^tt(3Rl4R,5SH-{4-fiuofophenyl)-4-hydroxy-3,5-dime ylfcarbonyftpyrrolkfin-l -yflnicotinonitrlle; 6-f(3S,4S)^4K3R14R,5S)^4-fluorophenytH-hy*co(y-315^methylpiperid^^ fiuwopyridin-2-yl)pyrrotidi'n-1-yl]pyridazifie-3-carbonitrile; 6-[(3S,4S)-3^5-lfuorapyridin-2-yl)^[(3R,4Rl5S)^hydroxy-3,5^irnethyl-4-phenylpiperidin-1- ylJcafbonyl}pyiTolklin-1-y)Jjyridazine-3-carboriitrile; e-KSS^^SHItSR^R.SSJ^^chlorophenylJ^+ydnDxy-S.S-dimethylpiperidin-l-yllcarbonylJ^KS- fluoropyridlr>-2-yl)pyfrolklin-1-yl]pyrida2tne-3-carbonilrile; 6-[(3S,4S)-3H;[(3Rr4Rl5S)^-(4-chtorophenyl)^^ydraxy-3,5-dime*hylpiperidin-1-yl]carbonyi}-4-(5- fluoropyridin-2-yl)pyrrolidBn-1-yl]pyridaziri-3(2H)-one; 6-[(3S,4S)-3-(5^anopyridin-2-yl)^-{t{3R,4R,5S)^(44luorophenyi)-4-hydroxy-3,5-dimethylpiperidin-1- yi]cartaony]}pyrroJidin-1-yl]pyridazine-3-carbonitrila; 6-f(3S,4R)-34[(3R,4R,5SH^4-fluorophenyl>-44i^^ methoxypyridiri-3-yl)pyrrolidin-1-yl]pyridazine-3-carfaonitrile; 6^(3S,4S)-3-fl(3R,4R,5S)-4-(4-fluorophenyl)^hydroxy-3)5-dimethylpiperidin-1-yl]carbonyl}-4-(5- m ethoxypyridin-2-yl)pyrroJidin-1 -ylJpyridazine-3-carbonitri[e; (3R,4R,5S)^4-ltuorophenyI)-1-{l{3S,4R)-1^5-fluoropyridin-3-ylh4-(6-methoxypyridin-3-yl)pyrrolidin-3- yl]carbonyl}-3,5-dHnethylpiperidin-4-ol; (3R,4R,5S)-1 -{[(3S,4S)-4-<5-chloropyridiiv2-yi)-l -pyridazin-3-ylpyrrolidin-3-yl]carbonyl}-4-(4- f!uorophenvl)-3,5-dimethylpip©ridin-4-Ql; e-[(3S,4S>-3^5-chloropyridin-2-yl)-4-{[(3R,4R,5S)^(4-fluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1- ylJcarbonyl}pyrrolidin-1-yl]pyridaan-3{2H)-one; S4(3S,4S>-3-(5-chloropyridin-2-yl)^t[(3R,4Rl5S)-4-(4-fluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1- yl]carbonyi}pyfrolidin-1-yl]-2-methytpyiidaEin-3(2H)-one; (3R.4R ,5S)-1 -{K3S,4S)-4-(5-chloropyridin-2-yl)-1 -[1,2,4Itriazoio[4,3-b]pyridazin-6-ylpyrrolidin-3- y!]carbonyf}-4-(4-ffuorophenyl)-3,5-dimethylpfperidfn-4-oi; (3R,4R,5S)-1-{K3S,4SM^5-chloropyridin-2-yO-^ (4-fluorop^»enyO-3,5-dimethylpiDeridin-4-Ql; 4^(3S,4S)^5K:hk>ropyridin-2-yl}^[(3R,4R15S}^ yl)carbonyf}pyrrolidin-1 -yl]pyrimidir>-2{1 HJ-oneg 4-{(3S14S)-3K5<^k>ropyridin-2-yl)^[{3R1^ yl]cartonyl}pyrrolidiri-1-yl]-1-m6lhylpyrimidiri-2(1H)-one; (3R,4R,5S)-1-{[{3S,4S)-4-(5-chloropyridin-2-yT)"1-(6-metlK>xypyridazin-3-yi)pyrrolW Huorqphenyl)-3,5-dimethyipiperidin-4-ol; eifSS^J-SKS^ioro-a-tluoropyricHn-Z-ylH-^R.^R.SSJ^^-fluorophenylH-hydroxy-S.S- dimelriylpiperidin-1 -yl]cait>onyl}pyrroUdin-1 -yl]pyridazine-3-carbonitrile; 64(3S,4S)h3-{5-one; 6i(3S,4Sh3H(3,5-difIuorapyridin-2-yO^H[{3Rt4R^^ 1-yl]carbonyi}pynrolidin-1-yl]-2-methylpyiidazin-3(2H)-one; e-[(3S,4S)-3Hl(3Rr4R,5S)-4-(4^hlorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1-yQcarbonyl}-4-(5- chloropyridin-2-yl)pyiTolidin-1-yl]pyriclazine-3-carb^ 1 -yljcar bonyJ}pyrrolidri-1 -yl]-2-methy^)yrktezln-3(2H)-one; (3R,4R,5S]h1-ff(3S,4S)^(5-ch]cfopyrfciin-2-ylM^ fluorophenyO-3,5-dime1!hylpiperidiri-4-Ql-I 64(3S,4S)^5-chlcTOpyridin-2-yQ^PMR>5S>^(4-flura y IJcarboriyf}pyrrolFdin-1 -yf]pyr idazin-3(2H)-ofie; 64(3S,4S)-3^5^hloropyridin-2-yO^[(3R,4R,5S)^(4-^ yJIcarbonyl}pyrrolidiri-1-yi]-2-methylpyridazin-3{2H)-one; {3R,4R^S)-1 -{[(3St4S)-4-(5-ch[oropyiidin-2-yl)-1 -[1 ^,4]tr1azQlo[4,3-b3pyrida2ln-6-ylpyrrofidin-3- y1}cart3onyl}-4-<4-flucHrophenyl)-3I5-dimethylpiperidin-4-d; {3R,4R,5S)-1 ^[(3S,4S)-4-(5-chloropyridrn-2-yl)-1 -im idazo[1,2-&]pyrida2in-6-ylpyrro)idi1n-3-yr]carbonyl}-4- {4-fluaTophenyl)-3,5-dtniethylpiperJdin-4-ol; 4^{3S,4SVH5onyl}-4-(5- chloropyridin-2-yt)pyrrolidin-1-yl]pyridazine-3-carboriilrile- e-USS^J^K^chlorapyridin^-ylJ-^CSR^R.SSJ^fS.^difluoraphenylH-by^roxy-S.S-dimethylpiperidin- 1 -yl]carbonyl>pyrralidin-1 -yl]pyridazine-3-carbonitrile; 6-[(3S,4S)^[(3RJ4R,5S)^-(4-chtorophenyl)^-hydroxy-3>tirimettiylpiperidin-1-y0carbonyl}-4-(5- chloropyridin-2-y()pyrrolidin-1-yi]pyridazin-3(2H)-orte; 6-r(3S,4S)-3-(5-chloropyndin-2-yl)-4-{[(3R,4R)5S}-4-(3,4-difruorophenyl)-4-hydroxy-3,5-dimethylpiperidin- 1 -yl]carbonyl}pyrralJdin-1 -yl]pyridazin-3(2H}-one; and the pharmaceutically acceptable salts, solvates (tnduding hydrates), and prodrugs thereof. Most preferably the compound is selected from: 6-[(3S,4S)-a^(5-chloropyridin-2-yl)-4-{[(3RJ4H,5S)-4^44luorophenyl>-4-h yiJ^ffbonj^ijrTiolklir^ 6-[(3S,4S)^{K3R,4R,5SM-(^cMoraplrenyl)-4-^ chtoropyridin-2-y0pyrrolidin-1-yfl-2-methyipynxiazin-3(2H)-one; 6-[(3S,4S)-3-(5^torppyvidin-2-ylH-W dimethylpiperidin-1 -yt]carbonyl}pyrrolidtn-1 -yl]-2-methylpyrida2Hn-3(2H)-one; 6-[(3S,4S)-3-(5-<*loropyridin-2-ylH^[(3R,4R,5S)^3,4-c^ 1 -yi]carbonyl}pyrroJidin-1 -yl]-2-me*ylpyridaziri-3(2H)-one; 6-[(3S,4S)-3-(5-chloropyricUn-2-ylM4[(3R,4R,5S)-4H;4^uor^^ yl]carrxjnyl)pyrroikiin-1-yl]pyridazin-3(2H)-one; 6-[{3S,4S)-3-(5-chloropyrid1n-2-yl)-4^[(3R)4fl]5S)^^ yUcarbonyl}pyrroIklhfi-1-yfl-2-methylpyridazin-3(2H)-one; &pS,4S)-3K[(3R.4R,5SH-(4-chlorophenyl)-4-riydroxy^315-dimefhylpiperidm chloropyrkfm-2-yl)pyrralidin-1-yqpyrklazine-3-carbonitrUe; 6-[(3S,4S)-3-(5-chloropyrldin-2-vl)-44[(3RJ4R,5S)^3,4^u 1 -yTJcarbonyl}pyrrolidffi-1 -yl]pyridazine-3-irjerazinv^^ .6-rJihydro-7H-pyrazolo[4.3- d]pyrim'tdin-7-one (sildenafil, particulariy present as the citrate salt); (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-mettiyi-6-(3,4-methylenedioxyphenyl)- pyraano[2^':6J]pyrido[3,4-b]indoJe-1 ,4-dione (IC-351 ortadalafil); 2-f2-ethoxy-5-<4-ethyl-piperazin-1 -yl-1 -sulphonyl^rjhenyq^-methyl-y-propyl-aH-irnklazolB, 1 - f][1,2,4]trrazin-4-Qne (vardenafil); 5-{5-AcetyJ-2-bu*oxy-3-pyridinyI)-3-e1hyt-2-<1 -ethyl-3-azetidiny!)-2,6- dihvdra-7H-pyraznlo[4,3-dlpyrimidin-7-ane; 5-(5-Acetyl-a-propoxy-3-wridtnyl)-3-ethvl-2-(1-isopropyl-3- a7eticiinyl)-2,6-dihydro-7H-pyrarolo[4,3-d3pyrim ldin-7-one; 5-l2-ethoxy-5-(4-ethylpiperazin-1 - ylsurphonyl)pyi1dii>^yl]-3-ethyl-2-[2wnetho^ 4-[(3- chfaro^metiiaxybenzyl)amino]-2-I<2S^ ylmethyl)pyrimidir»e-&<:arboxamide (TA-1790); 3-(1-methyl-7-oxo-3-propyl-6,7-ditiydro-1 H-pyrazolo[4,3- dlpvrimidi^5-yf)4*[2-(lHTiethylpyrrolidin-2-yl)eth^^ (DA 8159) and pharmaoeufically acceptable salts thereof. Particularly preferred NEP inhibitors for such combined products for the treatment of MED or FSD are the compounds exemplified in WO 02/079143. By cross reference herein to compounds contained in patents and patent applications which can be used in accordance with invention, we mean the therapeutically active compounds as defined in the claims (in particular of claim 1) and the specific examples (ail of which is incorporated herein by reference). If a combination of active agents is administered, then they may be administered simultaneously, separately or sequentially, in formulations which may be the same or different Biotoaical Assays Melanocortin receptor agonist activity: selectivity Measurement of in vitro agonist potency (ECgn) of compounds against melanocortin receptors type 1 and 3 (MC1 and MC3). Activation of melanocortin (MC) receptors by agonists results in activation of intracellular adenylate cyclase enzymes that synthesise the second messenger signalling molecule, adenosine 3\5'-cyclic monophosphate (cAMP). Changes in cAMP levels following treatment of recombinant MC1 and MC3 cell lines with test compound were measured and an MC1 and MC3 potency estimate (EC50) calculated as follows: Human embryonic kidney (HEK) or Chinese hamster ovary cell lines stably transfected with full length cDNA encoding human MC1 or MC3 receptors, respectively, were established using standard molecular biology methods. Test compounds were dissolved in dimethyl sulfoxide (DMSO) at4mM. 11 point half log unit increment dilution series of test compound, typically starting at 50uM were prepared in a buffer comprised of phosphate buffered saline (PBS), 2.5% DMSO and 0.05% pluronic F-127 surfactant. Freshly cuftePed ceUs at 30-90% confluence were harvested and re-suspended in Dulbecco's Modified Eagle's Medium (DMEM). CeHs (10,000 for MC3,20,000 for MCI) were added to the test compound dilution series in a 384 well assay plate and incubated for 1 hour at 37°C. The relative cAMP concentration in each welf was then measured using a p- galactosidase enzyme fragment complementation method purchased in kit form as the Discoverx cAMP if kit from GE Healthcare / Amersham Biosciences UK. In the case of MC1,3-lsobutyt-1-methyl)canthine (IBMX) at a concentration of 750 uM was included in DMEM as the cells were re-suspended for assay. The fluorescence readings taken from each assay well were converted into percent effect relative to maximum control wells corresponding to a concentration of alpha melanocyte stimulating hormone demonstrated to give a maximal effect Sigmoidal curves were fitted to plots of log10 inhibitor concentration vs percent effect using a custom made software application called SIGHTS and ECM estimates determined by the software as the concentration of test compound giving an effect half way between the bottom and top assymptopes of the sigmoidal dose response curve. Each experiment included an EC50 determination for alpha melanocyte stimulating hormone, which was used as a standard to track assay consistency and allow fair comparison between ECso estimates obtained in different experiments. MC5 and MC4 ECso activity was determined as described by assay protocols D and E, respectively, in US2005/0176772 (pages 28-30). Nle4. D-Phe7-g-MSH Inhibition at the MC4 Receptor Nle4, D^Phe7-a-MSH is a stable analogue of melanocyte-stimulating hormone (MSH), which is an agonist at the MC4 receptor (MC4R). Compounds can be evaluated for their ability to inhibit Nle4, D-Phe7-oc-MSH binding to membranes from cells expressing the MC4R using a competition binding assay versus [1!SI] Nle4, D-Phe7-a-MSH. Cells expressing the MC4R were subject to homagenisation and the membrane fragment isolated by differential centrifugation. CHO-CRE MC4R cell membranes were coupled to PVT-PEl-WGA SPA Beads type A for 2 hours, spun at 1000 RPM for 5 mins and suspended to a concentration of 300ug bead/ml (0.15ug membrane, 15ug bead per well). Bead/membrane mix was incubated with 0.06nM [125l] Nle4, D-Phe7-a-MSH and 11 half-log concentrations of competitor Bgand, in duplicate, in a total volume of 50ul buffer per well (25 mM HEPES, 1mM MgCfe, 2.5 mM Cads, 1% Pluronic F68, 1 complete EDTA protease inhibitor tablet/50 ml pH7). Non-specific binding was determined by the inclusion of 100nM SHU9119. The reaction was initiated by the addition of bead/membranes and plates were incubated at room temperature for 12 hours (the first hour on a plate shaker), after which the amount of radioactivity present was determined using a Wallac plate counter. Ki values were determined by data analysis using appropriate software. Preferably the compounds of the present invention exhibit a binding constant at the MC4 receptor expressed as an Ki value against Nle4, D-Phe7-cc-MSH of lower than about lOOOnM, more preferably tower Ihan SOOnM, yet more preferably lower than about 100nM and more preferably still lower than about 50nM, wherein said Ki value is deierrrsfced using She assay described above. Mle4. P-Phe7-ct-MSH Inhibition at the MC3 receptor Nle4, D-Phe7-a-MSH is a stable analogue of melanocyte-slimulating hormone (MSH), which is an agonist at the MC3 receptor (MC3R). Compounds can be evaluated for their abiity to inhibit Nle4, D-Phe7-a-MSH binding to membranes from cete expressing the MC3R using a competition binding assay versus [iasl] N(e4, D-Phe7-a-MSH. Cells expressing the MC3R were subject to homogenisation and the membrane fragment isolated by differential centrifugation. CHO-CRE MC3R cefl membranes were ooupled to PVT-PEI-WGA SPA Beads type A for 2 hours, spun at 1000 RPM for 5 mins and suspended to a final assay concentration of 800ug bead/ml (1.2ug membrane, 40ug bead per well). Bead/membrane mix was incubated with 0.06nM [12SI] Nle4, D-Phe7-a-MSH and 11 half-tog concentrations of competitor ligand, in duplicate, in a total volume of 50uJ buffer per well (25 mM HEPES, 1mM MgCfe, 2.5 mM CaCfe, 1% Pluronic F68, 1 complete EDTA protease inhibitor tablet/50 ml pH7). Non-specific binding was determined by the inclusion of 100nM SHU9119. The reaction was initiated by the addition of bead/membranes and plates were incubated at room temperature for 12 hours (the first hour on a plate shaker), after which the amount of radioactivity present was determined using a Wallac plate counter. Ki values were determined by data analysis using appropriate software. High Density Drug-Drug Interactions (DPI! 3uM Cocktail Screen A drug interaction is a situation in which a substance affects the activity of another drug, i.e. the effects are increased or decreased, or together they produce a new effect that neither produces on its own. Drug interactions may be the result of various processes but a relatively common one is where one drug affects the pharmacokinetics of another by inhibiting the cytochrome P450 that metabolises it Because of the importance of these phenomena, assessment of the DDI potential for new chemical entities (NCEs) is considered important early on in the drug discovery process. The DDI cocktail screen in human liver microsomes (HLM) is run in a fully automated fashion and the aim of the screen is to provide a single-point assessment of the DDI potential of new chemical entity (NCE; tested at 3 u.M) against the 4 primary cytochrome P450 enzymes, 1A2,2D6,2C9 and 3A4. The substrate cocktail approach for P450 DDI utilizes human liver microsomes together with isoform-specific clinical drug probes and permits the simultaneous measurement of the inhibition of P450 1A2, 2C9, 2D6 & 3A4 activities in a single incubation. This is run in high throughput with simultaneous detection of metabolites by LC-MS/MS. This method has been thoroughly tested and evaluated using standard compounds. The probe substrates used are given in the table below. (Table Removed) Appearance of the metabolite of each substrate is measured over time in the presence and absence of the NCE (test compound/inhibitor) at a concentration of 3 \sM. The compounds are assessed for their inhibitory potential as a percentage value and interpreted using the following scheme. These data are then used in conjunction with other measurements to evaluate the suitability of NCEs and to help with the design and progression of compounds. (Table Removed) AGRP Inhibition Agouti related protein (AGRP) is a high affinity endogenous antagonist/inverse agonist for the MC4 receptor {Lu et af., 1994, Nature 371: 799-802; Oilman et aL, 1997, Science 278:135-138). AGRP levels are upregulated by fasting (Mizuno & Mobbs 1999, Endocrinology. 140: 4551-4557) and therefore it is important to assess the ability of anti-obesity agents acting through the MC4 receptor to inhibit the binding of AGRP. It has been ascertained that this C-terminal fragment of AGRP contains the MC4R binding determinants (Yang et al., 1999, Mol Endocrinol 13; 148-155), therefore, compounds can be evaluated for their ability to inhibit AGRP binding to membranes from cells expressing the MC4R using a competition binding assay versus [12Sl]AGRP(87-132). To this end cells expressing the MC4R were subject to homogenisation and the membrane fragment isolated by differential centrifugation. CHO-CRE MC4R cell membranes (12|ig protein) were incubated with 0.3nM [125I]AGRP(87-132) and 11 half-log concentrations of competitor ligand, in duplicate, in a total volume of 100ui buffer (25mM HEPES, 1mM MgCfe, 2.5mM CaCI2l 0.5% BSA pH 7.0). Non-specific binding was determined by the inclusion of tuM SHU91ia The reaction was inftjated by the addition of membranes and plates were incabsted at roar, temperature for 2 hours. The reaction was terminated by rapid filtration onto GF/C fitters (presoaked in 1% PEI) using a vacuum harvester followed by five 200JJ1 washes of Ice cold wash buffer {Binding buffer containing SOQrnM NaCI). The filters were soaked in 50ul scintillation fluid and the amount of radioactivity present was determined by liquid scintillation counting. Ki values were determined by data analysis using appropriate software. Preferably the compounds of the present invention exhibit a binding constant at the MC4 receptor expressed as an KI value against AGRP of lower than about 1000nM, more preferably lower than 500nM, yet more preferably lower than about 100nM and more preferably still lower than about 50nM, wherein said Ki value is determined using the assay described above. Using this assay, compounds according to the present invention exhibit a binding constant at the MC4 receptor expressed as an Ki value against AGRP lower than "lOOOnM. Food Intake Study: To assess the efficacy of an MC4 agonist on food intake and body weight over a 24 hour period in the male rat Rats will be acclimatised to single housing and reverse lighting conditions (9.30am - 9.30pm) for approximately two weeks before the start of the study. Rats will tie acclimatised to Ihe Techincal Scientific Equipment* (TSE) cages approximately 24 hours prior to the study day. Rats will be randomly assigned to a treatment group on the morning of the study based on its weight (n=5/trealment). Each rat will either receive the MC4 agonist or vehicle orally just before lights go out. Following dosing the rat will be immediately placed back in to the TSE cage and lood intake and water consumption will be monitored throughout the course of the study (24 hours). Locomotor activity will also be monitored in the form of light beam breaks. At the end of the study rats will be killed by exsanguination under terminal anaesthesia by Isoflurane. Blood will be removed from the rat by cardiac puncture and analysed for drug concentration levels and biornarkers. The data are expressed as mean ± SEM and comparisons between the control and the treatment is analysed by ANOVA. Statistical significance is accepted at a level of p<0.05. In vitro Metabolism Rate Determination (Human Liver Microsome (HLM: Rat Liver Microsome (RLM) Assay) Many drugs are metabolised by the cytochrome P450 mono-oxygenase system-. This enzyme is found in high concentrations in the liver and is bound to the endoplasmic reticulum of the hepatocyte. The enzyme system can be obtained in semi-purified state by the preparation of the hepatic microsomal fractions. Determining a compound's in vitro half-life in such a system provides a useful indicator of metabolic stability. Materials And Reagents All reagents are ANALAR grade. I. 200mM Phosphate buffer (Sigma) - 100ml 1M Phosphate buffer pH7.4 dissolved with 400ml MilliQ water. If necessary, pH should be adjusted with concentrated orthophosphoric acid to pH 7.4, made up monthly and stared refrigerated (2-8°C). 2.0.1M WigCla.6H20 (BDH) - 2.032g dissolved in 100mi MilliQ water, and stored refrigerated (2-8°C). 3.0.02M NADP (Sigma) - 15.3mg dissolved sn 1000u1 MilliQ water - and then stored refrigerated (2-8°C) for further use. 4.0.1 M D-L tsocitric acid (Sigma) - 129mg dissoived in 5ml MilliQ water - and then stored refrigerated (2-8°C) for further use. 5. isocltric dehydrogenase, Type IV (Sigma) -stored refrigerated (2-8°C). 6. Stock solution of substrate (approximately 1mg/ml) in miscible organic solvents such as methanol, ethanol or water, stored refrigerated (2-8°C). 7. 50mM p-Nitroanisole (PNA) (Aldrich) - 7.65mg dissolved in 1ml methanol, and stored refrigerated (2-8°C) until ready for use. 8. 50uM p-NitrophenoJ (PNP) (Sigma) - 0.69mg dissolved in 100ml water and stored refrigerated (2-8°C). 9. 20% Trichloroacetic acid (TCA) (BDH) - 20g dissolved in 100ml MilliQ water, made up in amber glassware and stored at room temperature. 10.10M Sodium hydroxide (BDH) - 40g dissolved in 100ml NfflliQ water (care should be exercised when preparing this solution as this reaction is exothermic), made up in "safebreak" glassware and stored at room temperature. II. Hepatic or Supermix microsomes stored at -80°C should be defrosted immediately prior to use, kept on ice and dispensed. 12. MilliQ water. 13 .Thermostatically controlled shaking water bath set to give a temperature in the incubation of approx 37°C. 14. Reagent for termination of incubation {typically organic solvent, adkf or base). Methodology For In Vitro Rate Determination Using Hepatic & Supermix Microsomes The method outlined betow is for a total incubation volume of 1.5mt. 1. The following mixture is prepared in a test tube: (Table Removed) This volume is calculated for each new batch of isocitric dehydrogenase e.g. Protein concentration = ~\Qmg/mEnzyme activity = 3.3 unils/mg therefore Specific activity = 3.3 x 18 units/ml = 59 units/ml For a 1.5ml incubation 1.5 units of enzyme activity are required = —— x 1000 = 25.4ul. 2. Defrost microsomes at room temperature and add sufficient microsomes to give a final concentration of OJnmoi cytochrome P450/ml of incubation e.g. for a 1.5 ml Incubation, the volume of microsomes to be added is: P450 concentration required in incubation x incubation volume cytochrome P450 concentration in microsomal prep. 3. Add sufficient MiHiQ water to give a total incubation voiume of 1.425ml. 4. Remove 237.5ui of incubation mix and place in test tube for PNA positive control. Add 2.5u! of PNA solution, whiriimix, and put tube into a rack in the thermostatically controlled shaking water bath 5. Remove 100ul for no substrate control and dispense in test tube. Place test tube in a rack in the thermostatically controlled shaking water bath. 6. Add substrate to the incubation. The substrate should be at an initial concentration of 1uM. The volume of substrate required in the remaining 1.162.5ml incubation is calculated as follows: RMM x incubation vol.x. initial cone.in incubation 1000 x stock substrate solution cone. N.B. The volume of organic solvent added should not exceed 0.1% of Dhe total incuDafran volume. 7. Remove 1OOul of incubation mix into test tube for no cofactar control. Whiriimix and put into a rack in the thermostatically controlled shaking water bath. 8, Pre-incubate the tube containing the incubation mix, also positive control and no cofactor tubes in the thermostatically controlled shaking water bath set at 37°C for approx 5 min. 9 .Add MADP to initiate reaction (75ul to each 1.162.5ml incubation mix, 12.5ul to positive control tube and 5y\ to no substrate tube) and take first time point immediately. The PNA positive control, no cofactor control and no substrate tubes are incubated for the total incubation time. 10. Remove 1OOul aliquots up to 9 different sampling points from 0 to 60 min (usually 0t 3, 5,10,15, 20, 30,45 & 60 min) and terminate reaction. Longer incubation times can be used, but, after 120 min the microsomes deteriorate. The reaction may be terminated by addition of organic solvent, acid or base. At the end of the incubation process the no cofactor and no substrate controls in a similar manner i.e. terminate with the same reagent. 11. PNA positive control procedure: After the final sample has been taken, remove the positive control and add 1 m 120% TCA to this tube. Also prepare a tube containing 250|JI of a PNP standard at SOJIM, and add 1ml 20% TCA. Whiriimix both tubes and leave for approx 5 min to allow the protein to precipitate. Centrifuge both tubes for approx 5 min in an instrument set at 3500rpm. Remove 1 ml of supernatant and place into clean test tubes, discard the remainder. Add 1ml 10M NaOH to the supernatant, whiriimix, and leave to stand for approx 5 min. Blank spectrophotometer with distilled water at 400 nm then measure absorbance of the PNP standard against distilled water. The microsomal 4-nitroanisole O-demethylase activity is calculated as follows: Calculation of results Absorbance sample x nmotes PNP in standard fie 12.5nmoles) Absorbance PNP std x 60 x 0.125 = nmoles/min/nmol P450 The activity value from the incubation MUST be equal to or greater than 85% of the mean value of the batch used for the incubation to be valid. If this criteria is not met, then the incubation must be repeated. 11. Analyse samples {including no cofactor and no substrate controt) by a specific assay for the substrate to determine the disappearance kinetics, Analysis Of Data Data obtained using the procedure described above can be quantified in terms of the substrates in vitro intrinsic clearance (Clint). Providing that the substrate concentration is betow Km, the metabolism should be 1st order giving a log-linear plot of substrate disappearance with time. The in vitro half-life of the substrate can be determined by plotting the natural logarithm (In) of a measure of relative substrate concentration (e.g. drug/internal standard ratio) against time and fitting the line of best fit to thfe data The gradient of this line is the first order rate constant (k) for the substrate disappearance and is determined by regression analysis. This rate constant can be converted to the hatf-life according to the following equation :- Ln2 in vitro half-life (t1fi) = k Alternatively the rate constant can be converted to an intrinsic clearance (Clint) according to the following equation:- Clffit (ul/min/mg) = (k/protein concentration in incubation (mg/ml))*1000 Preferably the compounds of the present invention exhibit a clearance, as determined by the above assay, expressed as a value of lower than about 200pL/min/mg, more preferably lower than IQOuL/min/mg, yet more preferably lower than about 50 uL/min/mg and more preferably still lower than about 20uUmtn/"mg. Using this assay, compounds according to the present invention which have been tested exhibit a clearance lower than 200 uL/min/mg. Administration Methods Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutical^ acceptable excipients. The term 'excipienf is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the exccpient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, m Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995). Accordingly the present invention provides for a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutical^acceptable diluent or carrier. Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral (including buccal and sublingual administration), rectal, topical, parental, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (l) are administered orally or intranasally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, characteristics of the mammal to be treated (e.g. body weight), the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art. For the treatment of sexual dysfunction compounds of the present invention are given in a dose range of from about 0.001 milligram (mg) to about 1000 mg, preferably from about 0.001 mg to about 500 mg, more preferably from about 0.001 mg to about 100 mg, even more preferably from about 0.001 mg to about 50 mg and especially from about 0.002 mg to about 25 mg per kilogram of body weight, preferably as a single dose orally or as a nasal spray. For example, oral administration may require a total daily dose of from about 0.1 mg up to about 1000 mg, while an intravenous dose may only require from about 0.001 mg up to about 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fail outside of the typical range given herein. When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.0001 mg to about 1000 mg, preferably about 0.001 mg to about 500 mg, more preferably about 0.005 mg to about 100 mg and especially about 0.005 mg to about 50 mg per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.7 mg up to about 3500 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. (When Heating diabetes melSitus and/or hyperglycemia, as well as other diseases or disorders for which compounds of formula 1 are useful, generally safisfaciory results are obtained when $ie compounds of the present invention are administered at a daily dosage of from about 0.001 mg up to about 100 mg per kilogram of animal body weight, preferabfy given in a single dose or in divided closes two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 mg up to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants, the elderly and the obese. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual or sublingual administration by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing rnulti- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylceliulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001}. For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form, in addition to the drug, tablets generally contain a dismtegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substftuted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 wl% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include n^-oerystaWrie ceHutose, gelatin, sugars, polyethylene giycoL ratura! and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried mortohydrate, anhydrous and the fflte), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystaBine cellulose, starch and dibasic calcium phosphate cBhydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryi sulfate and poJysorbale 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryi sulphate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other possfafe ingredients include antioxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant and from about 0.25 wt% to about 10wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L Lachman (Marcel Dekker, New York, 1980). Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically cornprise a compound1 of formula I, a film-forming polymer, a binder, a solvent, a humectant, a piasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The compound of formula I may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula I may be in the form of multiparticulate beads. The fflm-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydracoftaids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other passible ingredients include antioxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foam ing agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coaler dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceuticat Technology On-line. 25(2), 1-14 by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, mtrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accompEshed using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral adRW?istpaticR may be formulated \c be anrasdiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed refease. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(dMactic-coglycolic)acid (PGLA) microspheres. The compounds of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for the purpose include gets, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresb and microneedle or needle-free (e.g. Powderject™, EMoject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention can also be administered intranasaiiy or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhafer or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuiiser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuiiser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant{s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an ofigolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is rnicronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenlsation, or spray drying. ^apsutes {made, for example, from gelatin or hydroxypropyiirre^yteeifaAose, bfcters and cartridges for ise m an inhaler or insufflator may be formulated to contain a powder mix of tfie compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /•• eucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the Ttonohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, pvridin-2-vl)-4-ffl3R.4R.5Sl-4-(4-^^ vilcarbonvftpvrrolidin-l-vnpvridaane-3-carbonitrite (Formula Removed) 3-Chloro-6-cyanopyridazine (prepared according to US 3,637,691) (20 mg, 0.14 mmot) was added to a solution of the pyrrolidine from preparation 10 (40 mg, 0.09 mmot) and N-ethyldiisopropylamine (0.06 mL, 0.37 rnmol) in acetonitrile (10 mL) and the mixture was heated at 70°C under nitrogen overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with cfichloromethane, increasing polarity to 5% methanol in dlchloromethane, to give the title compound (41 mg, 83%) as a white solid. 1H NMR (CD3OD, 400 MHz) S 0;4-0.6 (6H, 4 x d), 0.78-0.85, 1.60-1.69and 1.97-2.10(2H, 3 xm), 2.72-2.80 (1H, m), 3.00-3.23 (1H, m), 3.68-4.38 (8H, m), 6.99-7.08 and 7.38-7.50 (6H, 2 x m), 7.70 (1H, d), 7.80 and 7.94 (1H, 2 x dd), 8.58 and 8.61 (1H, 2 x d); LRMS (El+) 535 [MrfJ. Examples <3RAR.£S>-iKW3£4Sa-i-f6-1-ffl3S.4S)-4-(5-chtoropyn\Jin-2-vl^^ fluorophenvl)-3.5-dime1hvioiperidin-4-ol (Formula Removed) Sodium t-butoxide (31 mg, 0.32 mmol), 3-chforo-6-methoxypyridazine (34 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0) (8.5 mg, 0.009 mmoi) and 2,2'-bis(diphenvtphosphino)-1,1'-binaphthalene (11.5 mg, 0.0185 mmol) were added to a solution of the pyrrolidine from preparation 10 (100 mg, 0.23 mmol) in toluene (10 mL) and the mixture was heated at 80°C under nitrogen overnight. The solvent was removed in vacuo and the residue was taken up in ethyf acetate (25 mL), washed with water, dried (MgS04) and evaporated. Purification by column chromatography (silica) eluting with dichloromethane, increasing polarity to 5% methanol in dichloromethane, gave the title compound (48 mg, 40%) as a yellow foam. 1H NMR (CD3OD, 400 MHz) 5 0.4-0.62 (d+t+t, 6H), 0.86 (m, 1H), 1.65 (m, 1H), 1.93-2.08 (br, 1H), 2.75 (m, 1H), 3.17 (t, 1H), 3.74 (m, 3H), 3.95 (s, 3H), 3.96-4.21 (m, 3H), 4.32 (d, 1H), 6.98-7.1 (m, 5H), 7.38-7.48 (m, 2H), 7.79+7.48 (2 x dd, 1H), 8.56 (d, 1H); LRMS (El+) 540 [MH4! Examples (3a4fl^W4-clTtoftX3ltaivlM^^ vtlcarbonvlV-3.5-duTietiTVlpiperidin-4-ot (Formula Removed) To a solution of (3R,4R,5S)^(4-chlorophenyl)-1-{[(3S,4S)-4-(5-fluoropyridln-2-yf)pyrrolidin-3-yl]carfaonyi}-315-dimethylpiperidfn-4-ol (prepared by the same methods as used for the amine of preparation 10, starting from the aldehyde of preparation 17 and {3Rt4s,5S)-4-(4-chlorophenyl)-3,5-rjJmethylpiperidin-4-oL prepared according to international patent application publication number WO 2005/077935) (120 mg, 0.28 mmol) in dimethyf sulfoxide (2 mL) was added 3,6-dichloropyridazine (98 mg, 0.56 mmol), triethylamine (0.12 mL, 0.84 mmol), and caesium fluoride (13 mg, 0.084 mmol). The mixture was stirred al 110*0 under nitrogen for 3 hours. The reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX column, eluting with methanol to remove non basic material and dimethylsulfoxide, followed by 2M NH3 in methanol to elute the basic product The solvent was removed in vacuo to yield the title compound (74 mg, 49%) as a colourless gum. 1H NMR (CD3OD, 400 MHz) 8 0.44KJ.60 (6Hr 4 x d), 0.95-1.02,1.64-1.73 and 1.94-2.09 (2H, 3 x m), 2.69-2.79 (1H, m), 2.99-3.06 and 3.16-3.22 (1H, 2 x m), 3.74-3.79 (3H, m), 4.01-4.24 (4H, m), 4.32-4.36 (1H, m), 7.02-7.07 (1H, m), 7.29-7.70 (7H, m), 8.45-8.49 (1H, m); LRMS (El+) 544 [MH+]. Example 6 64(3S.4ST^ffl3R.4R.5S)-4-f4-chlorc>phenvn-4-h>^ fluoropvridin-2-vltovrrolidin-1-vnpvridazin-3(2l-»-one (Formula Removed) A solution of chloropyndazine from Example 5 (70 mg, 0.13 mmol) was dissolved in degassed acetic acid and stirred at reflux under nitrogen overnight The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane/methanol/aq. ammonia 95/5/0.5. This yielded the title compound as an off-white solid (37 mg, 55%). 1H NMR (CD3OD, 400 MHz) 8 0.43-0.59 (6H, 4 X d), 0.94-1.03,1.64-1.73 and 1.93-2.03 (2H, 3 x m), 2.65-2.78 (1H, m), 2.97-3.03 and 3.14-3,20 (1H, 2 x m), 3.62-3.79 (3H, m), 3.86-4.17 (4H, m), 4.31-4.35 (1H, m), 6.38-6.91 (1H, m), 7.30-7.42 f5H. m)„ 7.47-7.57 {1H, m), 7.63-7.68 (1Hr m), 8.44-8.48 (1H, m); LRMS (EM 526 [MH+]. Example 7 6-K3S.4SV3-W3R.4R.5SM-(4-chlorochenvfl^-hvdro^^ fluoropwkfiri-2-vnpvrrolrdin-1-vft-2-rnethvtPvrkJazin-3f2H)-one (Formula Removed) To a solution of the pyridazinone from Example 6 (30 mg, 0.057 mmol) in dimelhylformamide (2 mL) was added sodium hexamethydisllazide 1M in tetrahydrofuran (0.07 mL, 0.07 mmol) and lithium bromide (6 mg, 0.07 mmol). The mixture was stirred at room temperature under nitrogen for 30 minutes then methyl iodide (0.004 mL, 0.07 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (siBca) eluting with dichloromethane/rnethanol/aq. ammonia 95/5/0.5. This yielded the title compound as a yeBow solid. 1H NMR (CD3OD, 400 MHz) .8 0.44-0.59 (6H, 4 x d), 0.94-1.03, 1.64-1.73 and 1.95-2.04 (2H, 3 x m), 2.68-2.78 (1H, m), 2.95-3.01 and 3.14-3.21 (1H, 2 x m), 3.62-3.81 (6H, m), 3.87-4.17 (4H, m), 4.31-4.35 (1H, m), 6.87-6.90 (1H, m), 7.25-7.34 (4H, m), 7.38-7.42 (1H, m), 7.48-7.58 (1H, m), 7.64-7.69 (1H, m), 8.44-8.48 (1H, m); LRMS (EI+) 540 [MH+]. Example 8 (3R4R.5SH-ffl3S.4Sy4-{5-chloropvrldin-2-vn-1-^ dimethvl-4-pvTidin-2-vlomeridin-4-ol (Formula Removed) To a solution of (3Rl4Rr5S)-1-{[(3S,4S)-4-(5-chloropyridin-2-yl)pyrroiidin-3-yl]carbony!}-3,5-dimethyl-4-pyridin-2-yfplperidin-4-ol (prepared by the same method as used for the amine of preparation 10, starting from {3R,4s,5S)-3,5-dimethyl-4-pyridin-2-ylpiperidin-4-oi1 prepared according to international patent application publication number WO 2005/077935) (50 mg, 0.12 mmol) in toluene (5 mL), was added 3-bromo, 5-fluoropyridine (25 mg, 0.14 mmol), tris(dibenzylidineacetone)dipalladium {4.4 mg, 0.0048 mmol), BINAP (6 mg, 0.0096 mmol) and sodium tert-butoxide (26 mg, 0.27 mmol). The mixture was stirred at 80°C under nitrogen overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) editing with dichlorometiianeAnethanol/aq. ammonia 99/1/0,1, increasing polarity to 96/5/0.5. This gave the title compound (11 mg, 18%) as a yellow gum. 1H NMR (CDgOD, 400 MHz) 8 0.33-0.53 (6H, 4 x d), 0.81-0.93, 1.81-1.92 and 2.08-2.28 (2H, 3 x m), 2.69-2.78 (1H, m), 2.99-3.20 <1H, m), 3.61-3.94 (5H, m), 4.01-4.23 (2H, m), 4.34-4.42 (1H, m}, 6.81-6.90 (1H, m), 7.26-7.50 (3H, m), 7.70-7.94 (4H, m), 8.51-8.62 (2H, m); LRMS (El+) 510 [MH+J. Example 9 (m4R.5SV1-ff(3S,4S)-4-(5Kihloropwidin-2-vlH-PW pvridin-2-vtoiperidin-4-oi (Formula Removed) To a solution of (SR^R.SSJ-l-fltSS^^S-chlorap^icfin^-ylJpyrroli^ pyrkfn-2-ylpiperidin-4-o( (prepared by the same method as used for the amine of preparation 10, staring from (3R,4s,5S)-3,5-dimethyl-4-pyridin-2-y)p£ieridin-4-ol, prepared according to international patent application publication number WO 2005/077935) (50 mg, 0.12 mmol) In DMSO (2 ml_) was added 3-chloropyridaztne (28 mg, 0.24 mmol), caesium fluoride (18 mg, 0.12 mmol) and triethylamlne (0.05 mL, 0.36 mmol). The mixture was stirred at 100°C under nitrogen overnight. The reaction mixture was diluted with 10 mL ethyl acetate and washed with 3 x 20 mL of water. The combined aqueous extracts were extracted with 10 mL ethyl acetate and the combined organic extracts were washed with 10 mL brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (siflca) eluting with dichloromethane/methanol/aq. ammonia 99/1/0.1, increasing polarity to 95/5/0.5. This gave the title compound (16 mg, 27%) as a yellow gum. 1H NMR (CO3OD, 400 MHz) 8 0.20-0.37 (6H, 4x d), 0.91-1.13, 1.67-1.76 and 1.94-2.09 (2H, 3 x m), 2.54-2.62 (1H, m), 2.87-2.93 and 2.99-3.05 (1H, 2 x m), 3.61 -3.74 (3H, m), 3.86-4.08 (4H, m), 4.20-4.26 (1H, m), 6.83-6.88 (1H, m), 7.11 -7.44 (4H, m), 7.63-7.78 (2H, m), 8.30-8.46 (3H, m); LRMS (EI+) 493 [MH+]. Example 10 6-r(3S.4S)-3-(5-chloropvridin-2-vl)-4-(W3R.4R.5S)-4-(5-chloropvridin-2-vl)-4-hvdroxv-3.5-dimethvlpiperidin-1-vncarbonvl>pvrrolidin-1-vn-2-tnethvlpvridazin-3f2HVone (Formula Removed) To a solution of the carboxylic acid from preparation 15 (42 mg, 0.08 mmol) in dichloromethane (3 mL) was added N-efoyldiisopropylamine (£LfM mL, 025 mmol), t-hyxiroxybenzotriazole (15 mg, 0-095 mmol) and 1^3HJnmethytarninopropyl)-3-ethylcarbodiirnide and the mixture was stirred under nitrogen for 30 minutes. The amine from preparation 16 was added and the mixture was stirred under nitrogen overnight. The reaction mixture was diluted with dichtoromethane (20 mL) and washed with saturated NaHCQj (20 mL) and brine (20 mL). The organic layer was dried over MgS04, filtered and evaporated to give a yeftow oily solid. This was purified by column chromatography (silica), eluting with dichtoromethane and increasing the polarity to 95/5 dichloromethane/melhand to yield the title compound as yetiow solid (31 mg, 67%). 1H NMR (CD3OD, 400 MHz) <5 0.36-0.6 (m, 6H), 1.18 (br, 1H), 1.89 (br, 1H)„ 2.16 (br, 1H), 2.71 (m, 1H), 3.13 (m, 1H), 3.6-4.2 (s + m, 9H), 4.33 -3-(5-chloropvridin-2-vl)acrvlate (Formula Removed) n-Butyl lithium (2.5 M in hexanes, 34 mL, 85 mmol) was added dropwise to a solution of tert-butyl dielhylphosphonoacetate (19.1 mL, 81 mmol) in diethyl ether (80 mL) at -78°C under nitrogen and stirring was continued for 30 min. A solution of the crude aldehyde from preparation 2 (from 78.1 mmol of the iodide of preparation 1) in diethyl ether (20 mL) was then added dropwise, keeping the temperature below -65°C. Once the addition was complete the mixture was allowed to warm to room temperature over 2 hours before being cautiously quenched by the addition of saturated aqueous ammonium chloride (200 mL). The mixture was extracted with diethyl ether (2 x 150 mL) and the combined organic extracts were washed with brine (200 mL), dried (MgS04) and evaporated. The residue was purified by column chromatography (silica), eluting with pentane increasing polarity to peniane/ethyl acetate 8:2, to give the title compound (13.34 g, 74% over 2 steps) as an oil. 1H NMR (CDCI3, 400 MHz) S 151, (9H, s), 6.79 (IH, d), 7.35 (1H, d), 7.52, (1H, d), 7.66 (1H, dd), 8.55 (1H, d); LRMS (APCI+) 240 (MH4]. Preparation 4 f2EV-3-(5-Chloropvridin-2-vnacrvlic acid trifluoroaoetrc acid salt (Formula Removed) A solution of triiluoroacetic acid (10 mL) in dichloromethane (10 mL) was added dropwise to an ice cooled solution of the ester from preparation 3 (2.09 g, 8.7 mmol) in dichJoromethane (10 mL) and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, toluene (10 mL) was added and removed in vacuo and dichloromethane (10 mL) was added and removed in vacuo to give the title compound (2.44 g, 94%) as a red solid. 'H NMR (CD3OD, 400 MHz) 8 6.86 (1H, d), 7.64 (2H, m), 7.87 (1H, dd), 8.59 (1H, d); LRMS (APCI*) 184 [MH*]. Preparation 5 (4SM-Benzvl-3-f(2E)-3-f5-chloropvridin-2-vnprop-2-enovn-1.3-oxazolidin-2-one (Formula Removed) A solution of the acid from preparation 4 (2.44 g, 8.2 mmol) in tetrahydrofuran (15 mL) was cooled to -78°C under nitrogen. Triethylamine (2.85 mL, 20 mmol) was added dropwise followed by trimethylacetyl chloride (1.11 mL, 9.0 mmol), controlling the rate of addition so that the temperature stayed below -65°C. The mixture was then stirred at -78°C for 2 hours. "BuLi (2.5 M in hexanes, 4.26 mL, 10.7 mmol) was added dropwise to a solution of (4S)-4-benzyH,3-oxazoiidin-2-one (1.74 g, 9.8 mmol) in tetrahydrofuran (15 mL) under nitrogen at -78°C, controlling the rate of addition so that the temperature stayed below -65°C. After stirring at -78°C for 20 minutes the solution of oxazolidinone anion was added via cannula to the mixed anhydride solution at -78°C. The reaction mixture was stirred at -7B°C for 20 minutes then allowed to warm slowly to room temperature overnight The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL) and then concentrated in vacuo to remove the tetrahydrofuran. The solid precipitate was filtered and washed with diethyl ether to give the title compound (1.52 g, 54%} as a buff solid. The ether washings were evaporated to dryness, slurried in diethyl ether and filtered to give further product (0.42 g, 15%). 'H NMR (CDCI3, 400 MHz) 5 2.84 (1H, t), 3.37 (1H, d), 4.22 <2H, m), 4.78 (1H, m), 7.2-7.4 (5H, m), 7.51 <1H, d), 7.69 (1H, d), 7.86 (1H, d), 8.23 (1H, d). 8.62 (1H, s); LRMS (APCI4) 343 [MH*]. Preparation 6 (4^)-4-B^zyl-3-iI(3S.4S)-1-benzvl-4-(5-chtorc^ (Formula Removed) Trifluoraacetic acid (90 uL, 1.2 mmol) was added to a suspension of the oxazolidinone from preparation 5 (1.93 g, 5.6 mmol) in dichloromethane (20 mL) and A^benzyl-A/-(melhoxymethyl)trimethylsilylamine (2.3 mL, 9.0 mmol) was then added dropwise over 10 minutes. After the addition was complete the reaction was allowed to stir at room temperature overnight. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate solution {20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 20 mL) and the combined organic layers were dried (MgS04) and evaporated. The residue was purified by column chromatography (silica), eluting with ethyl acetate/pentane 2:8, increasing polarity to 2:3 to give the undesired (4S)-4-benzyl-3-{[(3Rl4R)-1-benzyl^(5n:hloropyridin-2-yl)pvrrolidin-3-yl]carbonvl}-1,3-oxazoiidin-2-one (1.16 g, 44%) as the first eluting component and the desired (4S)-4-benzyl-3-{[(3S,4S)-1-benzyl-4-{5-ch[oropyridin-2-yl)pyrrolidin-S-ylJcarbonylH.S-oxazofidin^-one (1.18 g, 45%) as the second eluting component. 1H MMR (CDC!3l 400 MHz) 8 2.75 (2H, m), 2.92 (1H, m), 3.20 (3H, m), 3.27 (1H, br), 3.68 (2H, br), 4.14 (2H, m), 4.23 (1H, m), 4.50 (1H, m), 4.67 (1H, m)r 7.10-7.40 (11H, m), 7.58 (1H, dd), 8.50 (1H, d); LRMS (APCi*) 476 [MHl. Preparation 7 Methyl (3S.4SV1 -benzvl-4-f5-chloropvridin-2-vl^Pvrrolidine-3-carboxvlate (Formula Removed) Sodium methoxkte (664 mg, 12 mmol) was added to a solution of the oxazolidinone from preparation 6 (1.17 g, 23 mmoO and dimethyl carbonate (1.03 mL 12 mmol) in dichiorometnane (15 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous layer was neutralised fay the addition of 2M HCI (~ 6 mL} and then concentrated in vacuo. The residue was triturated with acetonitrile (25 mL) and then filtered. Concentration of the filtrate gave (3S,4S>-1-benzyl-4-(5-chloropyrkJ«n-2-yl)pyrrolldine-3-carboxylic acid (123 mg, 16%) as yellow solid (see preparation 8 for spectroscopic data). The ethyl acetate layer was dried (MgS04) and evaporated. Purification of the residue by column chromatography (silica), eluting with ethyl acetate/pentane 2:8, increasing polarity to 2:3 gave the title compound (371 mg, 45%) as a colourless oil. rH NMR (CDCI3,400 MHz) 5 2.71 (1H, t), 2.97 <1H. t), 3.05 (2H, m), 3.23 (1H, m), 3.63 (5H, m), 3.82 (1H, q), 7.15-7.35 (6H, m), 7.55 (1H, d), 8.46 (1H, s); LRMS (APCI*) 331 [MH*]. Preparation 8 f3S.4SH-Benzvl-4-f5^hloropvridin-2-vf)pvrrolldine-3-carboxviic acid bis hydrochloride (Formula Removed) A solution of NaOH (135 mg, 3.3 mmol) in water (5 mL) was added to a solution of the ester from preparation 7 (371 mg, 1.1 mmol) in dioxane (10 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, taken up in water (10 mL) and neutralised with 2M HCJ (-1.7 mL). The mixture was then concentrated in vacuo, triturated with acetonitrile (20 mL) and filtered. The filtrate was acidified with 2M ethereal HCI and concentrated in vacuo to give the title compound (290 mg, 68%) as a solid. 1H NMR (CD3OD, 400 MHz) 8 3.40-4.20 (6H, m), 4.53 (2H, m), 7.40-7.60 (6Hr m), 7.81 (1H, d), 8.60 (1H, br); LRMS (APCI+) 317 [MM*]. Preparation 9 (3R.4R.5S)-Hff3S.4S^1-Benzvl-4-(5-chloropvridin-2-vltovn-olidin-3-vncanbonvft-4-(4-fluorophenvl)-3.5- dimethvlpiperidin-4-ol (Formula Removed) 1-Hydroxybenzotriazole (230 mg, 1.7 mmol) and 1-(3-dimethylamrnopropyl)-3-ethyl-carbodiimide hydrochtoride (354 mg, 1.8 mmol) were added to a solution of the acid from preparation 8 (522 mg, 1.5 mmol) in dichloromethane (10 mL) and triethylamine (1.03 mL, 7.4 mmol) and the mixture was stirred at roam temperature for 30 minutes before the addiSor. of (2rRM,5S^&ikK*oplher!yl)-3£-dimethylpiperidirt-4-ol hydrochloride (prepared according to US 2005/176772) (384 mg, 1.5 mmol). The mixture was stfrred at room temperature overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate (50 mL). The organic layer was washed with brine (50 mL), dried (MgSQvi) and evaporated. The residue was purified by column chromatography (silica), eluting with dichloromethane, increasing potarity to 5% methanol in dfchJoromethane, to give the title compound (546 mg, 71%) as an oil. 1H NMR (CD3OD, 400 MHz) 5 0.3-0.6 (6H, 4 x d), 1.23 (1H, m), 1.75-1.95 (2H, m), 2.72 (1H, t), 2.S5 (1H, m), 2.90-3.20 (3H, m), 3.45-4.05 (5H, m)t 4.32 (1H, d), 7.02 (3H, m), 7.20-7.50 (7H, m), 7.80, (1H, dd), 8.50 {1H, d); LRMS (APCI*) 522 [MH*]. Preparation 10 f3R.4R.5SH-fK3S.4Sl-4-f5-Chtoropwidin-2-vnD^ dimemylpiperidin-4-ol (Formula Removed) 1 -Chloroethyl chtoroformate (0.3 mL, 2.8 mmol) was added to a solution of the amide from preparation 9 (370 mg, 0.7 mmol) and N-ethyldiisopropylamine (0.27 mL, 1.6 mmol) in dichloromethane (10 mL) and the mixture was heated at reflux for 3 hours. After cooling to room temperature the solvent was removed in vacuo and the residue was partitioned between 10% aqueous citric acid (30 mL) and dichloromethane (30 mL). The organic layer was washed with water (30 mL), dried (MgSCv) and evaporated. The resulting dark oil was taken up in methanol (10 mL) and heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with 5% methanol in ofchloromethane, increasing polarity to 10% methanol in dichloromethane, to give the title compound (305 mg, 100%) as an oil.1H NMR (CDgOD, 400 MHz) 5 0.4-0.6 (6H, 4 x d), 1.00-1.06,1.77-1.82 and 1.98-2.05 (2H, 3 x m), 2.76-2.82 (1H, m), 3.00-3.20 (2H, m), 3.40-4.10 (6H, m), 4.36 (1H, rn)7.00-7.50 (5H, m), 7.85 and 7.95 (1H, 2 x dd)r 8.61 and 8.63 (1H, 2 x d); LRMS (APCI*) 432 [MH*]. Preparation 11 Methyl (3S.4SV4-(5-chloropvridin-2-vl)pvrroiidine-3-carboxvlate (Formula Removed) 1-Chloroethyl chtoroformate (2.33 mL, 21.4 mmol) was added to a solution of the ester from preparation 7 (1.77 g, 5.35 mmol) and N-ethyldiisopropylamine (2.1 mL, 12 mmol) in dichloromethane (10 mL) and the mixture was heated at reflux for 3 hours. After cooling to room temperature the solvent was removed m uaajo and the nacifiip was taken up In methanol {10 mL) and heated at reflux for 16 hours. The soSvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane, increasing polarity to 10% methanol in dicriloromethane, to give a mixture of the desired product and N-ethyldilsopropylamine as an oil. The oil was taken up in ethyl acetate (30 mL) and the resulting precipitate was filtered. The filtrate was concentrated in vacuo and the residue was taken up in acetonitrite (25 mL). The resulting precipitate was filtered to give the title compound (619 mg, 48%) as a white solid. 1H NMR (CDgOD, 400 MHz) 5 3.46 (m, 1H), 3.61-3.77 (m, 7H), 3.74 (s, 3H), 3.98 (m, 1H), 7.42 (d. 1H), 7.82 (dd, 1H), 8.57 ropvridin-2-vh-3.5-dimethvlpiPeridin-4-ol (Formula Removed) Step A: (3R.4s.5S)-4-f 5-chloropvridin-2-vlM -f4-methoxvben2V»-3.5-dimethvlpiperidin-4-ol A solution of 2-bromo-5-chtoropyr]dine (6.0 g, 31.2 mmol) in toluene (90 mL) was cooled to -78°C under nitrogen. n-ButyUithium (2.5M In hexanes) (15 mL, 37.5 mmol) was added dropwise over 12 minutes and the mixture was stirred at -78°C for 1 hour. A solution of (3f?,5S)-1-(4-methoxybenzyI)-3,5-dimethylpiperidin-4-one (prepared according to international patent application publication number WO 2005/077935) (6.93 g, 28.1 mmol) in toluene (15 mL) was then added dropwise over 10 minutes and the mixture was stirred at -78°C for a further 3 hours before being allowed to warm to room temperature. The mixture was quenched by pouring into saturated ammonium chkxide (100 mL) and, after stirring for 5 minutes, the mixture was partitioned between water (50 mL) and ethyl acetate (300 mL). The organic phase was separated and the aqueous phase was extracted with further ethyl acetate (2 x 300 mL). The combined organic extracts were dried over magnesium sulfate, filtered and then evaporated to dryness to give the crude intermediate. Purification by column chromatography (silica) elufjng with 2% methanol in dichloromethane, increasing polarity to 10% (10:1 melhanol:880 ammonia) in dichloromethane, gave (3R,4s,5S)-4-(5-chloropyridin-2-yl)-1-(4-methoxyben2yl)-3,5-dimethylpiperidrn-4-ol as an orange oil (8.48 g, 83%). Step B: (3R.4s.5SM-(5-chloropwidin-2-vl)-3.5-dimethvtoiperidin-4-ol The product from step A (6.56 g, 18.2 mmol) was dissolved in dry dichloromethane (100 mL), triethylamine (2.02 g, 20.0 mmol) was added and the solution was cooled to 5°C under nitrogen. 1-ChloroelihylchlorofonTiate (3.1 g, 21.9 mmol) was added dropwise to the stirred solution and on completion of addition the mixture was stirred for a further 2.5 hours at room temperature. The mixture was then washed with 10% aqueous potassium carbonate solution (3 x 50 mL) dried over magnesium sullate and evaporated to dryness. The crude oil was heated under reflux in methanol (100 mL) for 2.5 hours and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 mL) and methanol (10 mL), solid potassium carbonate (10 g) was added and the heterogeneous mixture was stirred for 30 minutes. The solid potassium carbonate was filtered off and the filtrate was evaporated to dryness. The crude product was then purified by column chromatography (silica) eluting with 10% methanol in dichloromethane, increasing polarity, to 20% (10:1 methanol:880 ammonia) in dichloroinetliane, to give the titfe compound (3.37 g, 77%) as a yellowish solid. 1H NMR (400 MHz, GDOs) 8 0.53 (3H, s), 0.57 (s, 3H>, 2.60-2.71 {mt 2H), 3.13 (q. 2H], 3.32 (d, 2H>h 7.43 (d, 1H). 7.7S (dd, 1H), 8.50 (1H, d), 9.58 (br, 1H), 9.84 (br, 1H); LRMS (APCI+) 241 and 243 [MH4]. Preparation 17 5-FlLH3ropvTidffie-2-carbaldenvde (Formula Removed) The title compound was prepared according to the methods of preparations 1 and 2, starting from 2-bromo-5-ffuoropyrIdine. This gave crude material containing tetrahydrofuran and diethyl ether which was used without further purification. *H NMR (CDCfe, 400 MHz) 8 7.57 (1H, dt), 8.03 (1H, dd), 8.62 (1H, d), 10.04 (1H, s); LRMS (APCT) 126 [Mrf]. Preparation 18 6-Formvinicotinonitrile (Formula Removed) A mixture of 6-methylnicotrnonitrile (10.0 g, 84.6 mmol) and iodine (20.0 g, 78.8 mmol) in dimethylsulfoxide (150 mL) was heated at 150°C under nitrogen for 20 minutes (reaction exhaust was scrubbed with bleach to remove dimethyl sulfide}. After cooling to room temperaUire saturated aqueous sodium bicarbonate (200 mL) was added carefully and the resulting mixture was extracted with toluene (3 x 100 mL). The combined organic extracts were washed with brine, dried (MgS04) and evaporated to give the desired product as an orange oil (5.65 g, 50%) which was used without further purification. 1H NMR (CDCI3,400 MHz) 5 8.06 (1H, d), 8.17 (1H, dd), 9.05 (1H, d), 10.12 (1H, s). Preparation 19 5-Methoxv-2-methvlDvridine (Formula Removed) 6-meihylpyridin-3-ol (5O.0 g, 0.458 mol) was added to a suspension of powdered KOH (103 g, 1.83 mol) in dimethylsulfoxide (750 mL) and the mixture was left to stir at room temperature under nitrogen for 1.5 hours. Methyl iodide (30 mL, 68.3 g, 0.481 mol) was then added dropwise over 1 hour to the dark brown mixture (exothermic). After stirring at room temperature for 1.5 hours water (1.0 L) was added and the mixture was extracted with ethy! acetate (2 x 300 mL). The combined organic extracts were washed with brine, dried (MgS04) and evaporated at 40°C on a rotary evaporator. The residue was purified by column chromatography (silica), eluHng with pentane, increasing polarity to ethyl acetate, to give the volatile product as a -1:1 mixture with ethyl acetate (40 g, -23.3 g product, 41%). 1H NMR (CDCI3, 400 MHz) 8 2.45 (3H, s), 3.79 (3H, s), 7.02 (1H, d), 7.08 (1H, dd), 8.16 (1H, d). Preparation 20 5-Methoxv-2-methvtavridine 1-oxide (Formula Removed) Chloroperbenzofc acid (51.3 g, 0.297 mol) was added portionwise to a solution of the compound of preparation 19 (40 g of a 1:1 mixture with ethyl acetate, 23.3 g, 189 mmol) in dichloromethane (1500 mL) and the mixture was stirred at room temperature for 2 hours. A solution of sodium, sulfite (45 g) in water (250 mL) was then added to the reaction and the mixture was stirred for 15 minutes,, at which point starch/KI indicator paper gave a negative test for the presence of oxidant. The organic layer was separated, dried over MgS04 and evaporated to give a pale yellow solid (54 g) which was a -1:1 mixture of the desired product and m-chtorobenzoic acid (rnCBA). This was taken on to the following step without further purification. 1H NMR (CDCfe, 400 MHz) 6 3.84 (3H, s), 6.97 (1H, dd), 7.19 (1H, d), 7.34 (1H, t, mCBA), 7.48 (1H, d, rnCBA), 7.94 (1H, d, mCBA), 8.04 (1H, s, mCBA), 8.36 (1H, d). Preparation 21 (5-Melhoxvpvridin-2-vrjmethanol (Formula Removed) Trifluoroacetic anhydride (28.2 mL, 203 mmoi) was added dropwise to an ice cooled solution of the product from preparation 20 (-135 mmol) in dichloromethane (500 mL), the mixture was allowed to warm to room temperature and stirred overnight Tic analysis indicated still largely starting material so a further portion of trifluoroacetic anhydride (15 ml_ 108 mmol) was added dropwise and the mixture was allowed to stir far a further 27 hours. The reaction was quenched by the cautious addition of methanol (250 mL) and left to stir for 30 minutes before being concentrated in vacuo. 2.5 M sodium hydroxide (100 mL) was then added cautiously and the mixture was extracted with dichloromethane (4 x 100 mL). The combined organic extracts were dried (MgS04) and evaporated to give the desired product (12 g, 64%) contaminated with recovered starting material (-15 mot%). 1H NMR (CDCI3, 400 MHz) 5 3.80 (3H, s), 4.40 (1H, br), 4.66 (2H, s), 7.16 (1H, dd)r 7.20 (1H, d), 8.17 (1H, d). Preparation 22 5-Methoxvpvridine-2-carbaldehvde (Formula Removed) Mn02 (97.0 g, 360 mmol) was added in one portion to a solution of the alcohol from preparation 21 (12 g, 86 mmol) in dichloromethane (500 mL) and the resulting suspension was stirred at room temperature for 64 hours. The reaction mixture was filtered through Celite® and the solvent was removed in vacuo to give the desired product (8.6 g, 73%) contaminated with 5-methoxy-2-methylpyridine 1-oxide (15 mol%) as an orange on. 'H NMR (CDCI.3, 400 MHz) § 3.93 (3H, s), 7.26 <1H, dd), 7.91 (1H, d), 8.37 (1H, d), 9.94 (1H, s). CLAIMS 1. A compound of formufa (1): (Formula Removed) wherein one of X and Y is N and the other is CH, R is F, Cf, CN, CFa or methoxy, with the proviso that when Y is N, R is not F or CI, R1 is phenyl, 2-pyridyl, C3-Ce cycloalkyi or CH-[Cs-Ce cycloalkyi), wherein the ring moiety is optionally substituted by one or more substituents independently selected from F, CI, CN, methyl and methoxy, R2 is H, F or CI, with the proviso that when Y is N, Ra is not F or CI, Het is a 6-membered ring containing one or 2 N atoms, wherein the ring is either aromatic, or contains 2 double bonds in the ring and a =0 substituent, which ring is optionally substituted by one or more substituents independently selected from F, CI, OH, CN, methyl, ethyl, NHa, NHCH3, N(CH3)Z and methoxy, or alternatively, Het is a 6-membered ring containing one or 2 N atoms fused at the 3,4-positions, relative to the attachment to the pyrrolidine ring, to a 5-membered aromatic ring containing one or two further N atoms, which 5-membered ring is optionally substituted by OH, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof. 2. A compound according to claim 1 wherein X is N and Y is CH, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof. 3. A compound according to any one of claims 1 or 2 wherein R is chloro, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof. 4. A compound according to any one of claims 1, 2 or 3, and the pharmaceutical!/ acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein R1 is phenyl optionally substituted by one or more substituents independently selected from F, CI, CN, methyl and methoxy. 5. A compound according to claim 4, and the pharmaceutically acceptable sate, solvates (including hydrates), and prodrugs thereof, wherein R1 is phenyl, 4-chlorophenyl or 4-fluorophenyi. 6. A compound according to any on of claims 1, 2 or 3, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein R1 is Ca-C6 cycloalkyl. 7. A compound according to any on of claim 6, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein R1 is cycbpropyl orcyclohexyl. 8. A compound according to any one of claims 1, 2, 3, 4, 5, 6 or 7, and the pharmaceutically acceptable sails, solvates (including hydrates), and prodrugs thereof, wherein Rz is H or F. 9. A compound according to claim 8, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein R2is H. 10. A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein Het is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihyclropyridin-3-yl, 2-oxo-1,2-dahydropyrimidin-4-yl, 6-oxo-1,6-dihydropyrimidin-4-y], 2-oxo-1,2-dihydropyridin-4-yl, imidazo[1,2-b]pyridazin-6-yl, [1,2,4]triazoio[4,3-b]pyridazin-6-yl or 6-oxo-1,6-dihydropyridin-2-yl, optionally substituted by one or more substiluents independently selected from F, CI, OH, CN, methyl, ethyl and methoxy. 11. A compound according to claim 10, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein Het is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl or 6~oxo-1,6-dihydropyridazin-3-yl, optionally substituted by one or more substituents independently selecledlrom OH, CN, F, methyl and methoxy. 12. A compound according to claim 11, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein Het is pyridin-2-yl or pyridaz5n-3-yl, each of which is substituted at the para-position relative to the bond linking to the pyrrolidine moiety, by OH, CN or methoxy. 13. A compound according to claim 12, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof; wherein Het is pyridazin-3-yl substituted at the para-position relative to the bond linking to the pyrrolidine moiety, by OH, CN or methoxy. 14. A compound according to claim 1 selected from: 6-[(3S,4S)-3-(5-chloropyridin-2-yl)-4-{{3R,4R,5S)-4-(4-flourophenl)-4-hydrox-3,5-dimethylpiperidine-1-yl]carbonyl}pyrrolidin-1-yl] pyridazine-3-carbonitrile; 6-{(3S,4S)3-(5-chloropyridin-2-yl)-4-{{3R,4R,5S)-4-hydoxy-3,5-dimehtle-4-phenylpiperine-1-yI]carbony}pyrrolidin-1-yl] pyridazine-3-carboriitrile; 6-[(3S,4S}-3(5-dhloropridin-2-yl)-4-{{3R,4R,5S)-4-hydoxy-3,5-dimehtle-4-phenylpiperine-1-yl]carbomnyl}pyrrolidin-1-yl]pyridazirie-3-carbonitrlle; 6-I(3S,4S)-3-(5-chloropyricrm-2-yl)-4-{{3R,4R,5S)-4-hydoxy-3,5-dimehtle-4-phenylpiperine-1-yI]carborivl}pyrralidin-1-yl]pyrldazin-3(2H)-one; 64(3S,4S>-3-(5-chloropyridin-2-yl)-4-{{3R,4R,5S)-4-hydoxy-3,5-dimehtle-4-phenylpiperine-1-yl]carbonyl}pyfrolidin-1-yl]-2Knethy[pyridazin-3(2H)-one; 6-I(3S,4S)-3-{{3R,4R,5S)-4-(4-chloroophenyl)-4-hydroxy-3,5-dimethylpiperine-1-yl]carbonyl}-4-(5-chtoropyridin-2-yl)pyrrolidin-1-yll-2-methylpyridazin-3(2H)-one; 6-{{3S,4S)-3-(5-chloropyridine-2-l-4-4-{{3R,4R,5S)-4-(5-Chloropyridin-2-yl)-4-hydoxy-3,5- dimethytpiperkrm-1-yl]carborny]proolidine-1 -yl]-2-methylpyridazin-3(2H)-one; 61(3S,45)-3-[5H;hkjfopyridin-2-yl]-4K[(3R,4R,5S)-4-(3,41 -{[(3S,4S)-4-[5-chior opyridJn-2-ylH -(6-methoxvpyridazin-3-yl)pyrrolidne-3-yl]carbonyl}-4- cyclopropyl-3,5-oJmethylpft)eridin-4-ol; (3R,4R,5S)-1-[(3S,4S)rcpyridin-2-ylH-(5-flouropyridine-3-yl)pyrrolidne-3-yl]carbonyl}-4- fluorophenyl)-3,5-dimethylptperidin-4-ol; 6-[(3S,4S)-3-(5-chloropyridBn-2-yl)-[{[(3R,4RF5SH-(4-flouropryidin-3-henyl)-4-hydroxy-3,5-dimethylpiper y]]carbonyl}pyrrolidin-1-yl]nicotinonitrile; 6-[(3S,4S)-3-[[(3R,4R,SS)-4-{4-fluorcphenyl)-4-hydoxy-3,5-imethylpiperidin-1-yl]carbonyl}-4-(5- fluoropyridin-2-yi)pyrrolidin-1-yl]pyrida2ine-3-carbonifrile; 6-[(3S,4S)-3-(5-fluoropyridin-2-yl)-[{[(3R,4R,5S)--hydoxy-3.5-dimethyl-4-phenyipiperidin-1- yl]carbonyl}pyrroikfm-1-yl]pyrkiazine-3-carbonitrile; 6-[(3S,4S)-3-{[(3R,4R,5S)-[(4-chlorophenyi)-[-hydroxy-3,5-dimethyiptperidin-1-yl]carbonyl}-4-(5- fluoropyridin-2-yl)pyrrolidin-1-yl]pyridazine-3-carbonitrile; 6-[(3S,4S)-3K[(3Rt4R,5S)-[(4-chlorophenyl)-hydroxy-3,5-dimethyiptperidin-1-ylilcarbonyl}-4-(5- fluoropyridin-2-yl)pyrrolidin-1-vl]pyridazin-3(2H)-one; 64(3S,4)-5ayanopyridin-2-yl]-4-flouroyl}pynralitlidine-l -yi]pyrida2ine-3-carbonitrite; 6~[<3S,4fl)-3-a{3R,4R,5S)-[(4-fluorophenytM4i-[ metiiox-pyridiri-3iir0pyn'olklirv1-yl]pyrkla2irie-3-carbcmitrile; 6-[(3S-4S)-3-{[(3R ,4R,5S)-4-(4-f luorophenyl)-4-hydroxy-3,5-dim ethyipiperidin-1 -yl]carbonylJ-4-(5-methoxypyridin-2-y0pyrralidin-1-yQpyridazlne-3-carboriitrile; (3R,4R-[)-[4-fluorophenyt)-H[(3S14R)-1-(5-fluor-[ yl]carbonylJ-3,5-dimeWT(ylpiperidin-4-ol; (3R,4R,5S)-H[(3S,4S)-4-(5-chlchopyridin-2--[-[ fiufflrophenylJ-S.SHdimelhylpiperidin-[ol; 6-[(3S,4S)-[(5<3-[5-ch[ofopyridLn-2-yl] yt-[artwnyl}p-[ralkljn-1-yl]-2Hne1hylpyt1da2in-3(2H)-oiie; (3R,4iR-[S)-1 -a(3S,4S)-4-(5-chloropyridiri-2-yl)-1 -[1,2t4]triazolo[4,3-b]pyridaznn-6-ylpyrro1idin-3-yl]caitionyl}-4-[4-fluoraphenyi)-3yl-dimethylpiperidin-4-ol; (3R,4R,5S)-1 -[[(3S,4S)-[(5<-[loropyridin-2-yl)-1 -imidazo[1 -[-blpyridazin-e-ylpyrralidin-ai-yllcarbonyl}-(4>-fluofopheriyl)-3,5-dimethylpiperidin-4-ol; 4-[(3S,4S)-(5K3hloropyridin-2-yl)-[[(3R,4R,5S)-4-(4-fluorophenyl)-44iydroxy-3,5-dimeftylpiperidin-1-yt]carbonyljpyrrolidin-1 -yljpyrimidin-2(1 H)-one; 4-[(3S,4S)-3-(5chloropyridin-2-yl)-44[(3R,4R,5SM-[4-[ yijcarbonyljpyrrdidin-l -yJJ-1 -methylpyrim idin-2(1 H)-one; (3R,4R5SH4[(3S,4S)-4-{5-chloropyridin-2-y1)-1-(-[ flucwroplier)yl)-315-dinelhylpiperidin-4-ol; 6-[(3S(4S)-3-(5-[ioro-3-{luoropyridin-2-yl>-44[(3R,4R,5S)-4-(4-fluorophenyl)-4-hydroxy-315- dimethylplperidin-1 -yl}carbonyl}pyrrolidiiv1 -yl]pyridazine-3-carbonitrile; 6-[(3S,4S)-3-[5-chiloro-3-fluoropyridirt-2-yl)-4-{[(3R,4R,5S)-4-(4-fluorophenyl)-4-hydroxy-3,5- dimethylpiperidin-1 -yijcarbonyl}pyrrolidin-1 -yl]pyridazin-3{2H)-one; 6-[(3S,4S)-3H5-chloro-3-fluOTopyridin-2-yl)-[{[(3R,4Rr5S)-4-(4-fluoropheny1>-4-hydroxyl]3J5- dimethylpiperidini-1 -yl])carbonyl}pyrrolldin-1 -yl]-2-methylpyridazin-3(2H)-one; 6-[{3S,4S)-3-[315KlifluaropyrkJin-2-yl)-[{[(3R,4R15S)-[(4-fluorophenyl)-44iydroxy-3,5-dim-[ 1 -yflcarbariyli}pyrro(id?n-1 -yl[pyrldazine-3-carbonitrile; eHXSS-[SJ-S-tS.S-[IiJKXopyridin-[-yl[-[-[R-[.SSM-[-fluor-[-[ 1 -yl]carbonyl}pyrrofidin-1 -yl]pyridazin-3<2H)-one; 6-[(3S,4S)-3-(3J5-[muoropyridin-2-yl)-[[(3R14fl15S)-[(4-fluorophenyl)-[-liydroxy-31S-dimethylpiperidin- 1 -yf|carh>onyl}pyrrolidin-1 -ylJ-2-methylpyridazin-3(2H)-one; 6-[(3S,4S)-3-{[(3R,4RJ5S)-[-{4-chlorophenyl)-4-hydroxy-$$$$$$$3,5-3-[5-chlorcfiyridin-2-yl)-[Q(3R,4R,5S)-44iydroxy-3,5-[imethyl-4-phei-[ y0carbonyl}pyrrolidin-1 -yl]pyridazine-3-carbonitrile; 6-[(3S,4S]h3-(5-chilorq3yrfdln-2-yl)-[{[(3RI4R,5SH-Mroxy-3,5-1 -{[(3S,4S)-4-{5-chloropyridin-2-yl)-1 -imidazo[112-b]pyridazin-6-ylpyrrolkfin-3-yr|carboriyi}-4- (4-fluoropheny0-3,5-drmethylpiperidin-4-ol; 4-[(3S,4S)-3-{5-chloropyridin-2-yl]-44[{3Rl4R,5S)-4-(4-fluorophenyl)-4-hydroxy-3,55S)-4-(4-fIuorophenyO-4-hydroxy-3,5-dimethyipiperidin-1- yl]carbonyl}pyrrolidin-1 -yl]-1 -methylpyrimidin-2(1 H)-one; 6-[(3S,4S>-3-[5-chioro-3-fluoropyridin-2-yl)-4-{[(3R,4R)5S)-4-(4-fIiJorophenyl)-4-hydroxy-3,5- dimethy{piperidin-1 -yi]carbonyl}pyrrolidin-1 -ylJpyridazine-3-carbonitrite; 6-{{3S)4S)-3-(5-chloro-3-fluoropyridin-2-yl)-4-{[(3R,4R,5S)-4-(4-fluorophenyl)-4-hydroxy-3,5- dimethylpiperidin-1 -yi]carbonyl}pyrrolidin-1 -yflpyridazin-3(2H)-one; 6-[(3S,4S)-3-(5-chloro-3-fluoropyridin-2-yl)-4-{[(3R,4R,5S)-4-(4-fluorophenyl)-4-riydrQxy-315- dimethylpiperidin-1 -yl]carbonyl}pyrrolidin-1 -ylJ-2-m ethylpyridazin-3(2H)-one; -[(3SJ4S)-3-(315-[ffluafopyridin-2-yl)-[[{3R,4R)5S)-[-(4-fluorophenyl)-4-l-[roxy-3)5-[ime-[ 1 -yllcarbanyllfjwroltdin-l -ylJjyridazine-3-carbonitrife; 6i(3S,4S)-3-(3,5-difluoropyridJn-2-yl)-4-[[(3R,4R,5S)-4H4-fIuoraphenyO-[-hyxfroxy-315-dfm 1-yi]c-[l)onyJlpyrfdtdfn-t-yf]pyfidazin]-3(2H}-c)ne; 6-[(3S,4S)-[{3-[dffluoropyridin-2-yl)-4-{E(3R,4R-[)-4-[4-fluOTophenyl)-4-hydroxyl]3,5-dfm 1 -yljcarbonyijpynrolldln-l -yf]-2Hfneihylpyrkiazin-3(2H)-one; 6-[(3S,4S)-3-[pR,4R,5S)-[(4-chkMrophenyl)-[hydrox-[ chkwopyridirv-2-yl)pynrafidSn-1-yIg3yfidazine-3-carbonitrile; 6-[3S,4S)-3-[5-chloropyridin-2iriW[(3R,4R,5S)-[(3/-[difliiOT-[ 1 -yt]carlx)(nyl}pyrro§din-1 -yl]pyridazine-3-carbonitrile; 6i(3S,4S)-3-{[(3R,4R,5SM-[4-chtorophenyl)-[hvdroxy-3,5-[-[ (±loropvridin-2-yl)pyrroltdih-1-y1]pyridazin-3{2H)-one; 6-[(3S,4S)-(5K:hlorapyridin-2-yH4[(3R14R-[)-[-(314-[ifluorophenyl)-[-hydroxyl]31S-[imethylpiperidin-1 -yl]carbonyl}pyrfOlidin-1 -yl]pyridazin-3(2H)-one; and the pharmaceutieally acceptable salts, solvates fmciuding hydrates), and prodrugs thereof. 16. A compound according to claim 15 selected from: 6-[(3S,4S)-345-chil«opyrkJin-2-yl)-[{[(3-[ yljcarbonyl}pyrrofidin-1 -yl]pyridazine-3-carbonitiile; -[{3S,45>-34[(3R,4R,5S)-[(4-chlorcphenyl)-44iydroxy-3,5sJiimethvipiperidin-1-yl]carboriyl}-4-(5- chlwopyridiiv2-yl)pvrroJioln-1-ylh2-rnethylpyridazin-3(2H)-one; 6i(3SJ4-[)-[3-[5-chloropyridirH2-yl}-4-{[(3a4R,5S)-4-(5-criloropyridin-2-yl)-4-hydroxy-3,5- dimethy!piperio5n-1-yi]caitonyl}pyrrdidin-1-vll-2-methylpyridazin-3(2H)-one; 6{(3S,4S)-3-(5-chloropyridin-2-ylH-[[(3R,4R,5SM-(3,4-difluoro-[ 1 -yl]carbonyi}pyrrofidin-1 -yf]-2-methyfpyridaan-3(2H)-one; 6-[(3S,4S)-3K5s:hlorap-[din-2-yl)-[[(3R,4R,5S)-[(44[uoroph yl]cartonyl}pyrrolidin-1-yl]pyridazin-3(2H)-ane; 6i(3S,4S)-3-(5-chloropyridin-2-ylM-[3R,4R,5S)-[44luorophenyf)-[h yl]carbonyl}pyrrolidin-1-yi]-2-methylpyrida2dn-3{2H)-one; 6-[(3S,4S)-{[(3R,4R,5S)-4-[4-[h!oropheny0-[hydroxy-3,5-dimetJiylpiperidin-1-yllcarbonyi}-4-{5- chloropyridin-2-yl}pyrrolidin-1-ylJpyridazine-3-carbonrtrile; 64(3Sr4S)-[(5K;hk>ropyridin-2-y])-4-{[(3R,4R,5S)-4-{3,4-difiuorophenyl)-4-hydroxy-315-dimethylpiperidin- 1 -y|]carbonyl)pyrrolidin-1 -yl]pyridazine-3-carbonrtrile; 64(3S,4S)-[-[(3R,4R,5S}-4-(4-[hlorophenyl)-44iydroxy-3,5-dime crtloropyridin-2-yl)pyrrolidin]1-yl]pyridazin-3{2H)-one; 64(3S,4S)-3-(5-chloropyridin-2-yl)-4-{[<3R,4R,5S)-4<3,4-dif-[ 1 -yl]carbonyl}pyrrolidin-1 -yl]pyridazin-3(2H)-one; and the pharmaceutieally acceptable salts, solvates (including hydrates), and prodrugs thereof. pharmaceutical composition comprising a compound according to anyone of claims 1,2,3,4,5, 6, 7,8, 9,10,11,12,13,14,15, or 16, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, and a pharmaceutically acceptable diluent, carrier or adjuvant A compound according to any one of claims 1, 2, 3, 4, 5,6, 7,8, 9,10,11,12,13,14,15, or 16, or a pharmaceuticaily acceptable salt, solvate (including hydrate), or prodrug thereof, for use as a medicament A compound according to any one of claims 1,2, 3, 4, 5, 6,7, 8, 9,10, 11,12,13,14,15, or 16, or a pharmaoeuiicaHy acceptable salt, solvate (rncJudlng hydrate), or prodrug thereof, for use as a medicament for the treatment of a disorder which would benefit from MC4 agonism. A compound according to any one of claims 1, 2, 3, 4, 5,6, 7, 8, 9,10,11, 12,13,14,15, or 16, or a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof, for use as a medicament for the treatment of a condition which would benefit from treatment with a MC4 receptor agonist, such as sexual dysfunction, obesity, diabetes or a urological condition. A method of treating a disorder which would benefit from agonism of the MC4 receptor which comprises administration of a therapeutically effective amount of a compound, salt, solvate or prodrug according to any one of claims 1, 2, 3, 4,5, 6,7, 8, 9,10,11, 12,13, 14, 15, or 16, or a pharmaceutically acceptable salt, solvate (Including hydrate), or prodrug thereof, or pharmaceutical composition thereof, to a patient in need thereof. A method according to claim 21 wherein the disorder is a sexual dysfunction, obesity, diabetes or a urological condition. A compound, salt, solvate, prodrug, process, method of treatment, pharmaceutical composition, substantially as described herein.